Bis-isoindole quaternary salts



The general structural formula of the compounds de rived from each ofthe anhydrides listed above are as 2 807 624 follows: BlS-ISOINDOLEQUATERNARY SALTS (1) From phthalic anhydride Charles H. Grogan, FallsChurch, Va., and Leonard M. X- X- CH Rice, Baltimore, Md., assignors toThe Geschickter CH Fund for Medical Research Inc., Washington, D. C., 2/a)..- acorporation of New York OH H; o

No Drawing. Application December 30, 1955,a,w-Bis-(-2-lsolndolinyl)-alkanes dlmethonlum dlhalide Sena 556,435 (2)From cis-A tetrahydrophthalic anhydride:

1 Cl Cl. 260-319 1 aims Kfi i CH N(CH2)'.N This invention relates toorganic chemical compounds OH/ E c a CH and particularly to compoundshaving therapeutic properties and useful in the treatment ofcardio-vascular gg gg g mane diseases.

The compounds embraced by this invention are alpha, (3) Fromhexahydmphthahc anhydnd omega, bis-isoindole quaternary salts.

It has been found that the bis-isoindole quaternary (OH) l salts possessunexpected hypotensive properties which are not possessed by the basesthemselves or the simple salts. Both the simple salts and the quaternarysalts of the bases were tested on animals and the simple salts such asthe hydrochloride were found to be inactive while the bis-methoniumquaternary salts were found to be surprisingly active hypotensive agentswith very low toxicity, the L. D. 50 in rats for some being over 100 mg.per kg. 3 J

OIHQ N(OH2)-N H2 The fundamental object of the present invention is theCH (E g \CH provision of novel organic compounds. HI 0 Ia,w-BiS(4,5,6,7,8,9 hexahydro-2-isoind0linyl) alkane dimethonlum salts(4) From 3,6-endomethylene-cis-n -tetrahydrophthalic anhydride:

An equally imPOttQmt object is the PmViSiOI} of them a,w B1S-(4,7,8,9tetrahydro-4,7-end0n1ethano-2ds0lndolinyl) peutic agents useful in thetreatment of cardro-vascular n a e di et oniu salts diseases,particularly hypertension. 3 5 From 3 6 dox he ah d h th 1 nh d de.

The compounds falling within the scope of the present en y X y mp a m ay n invention may be represented by the following generalized CH X- X-CH f0 1 grap 1c rmu a.

i $11. on. \OHI I allmne dimethonlum salts (6) Froml,2-dimethyl-3,6-endoxyhexahydro-phthalic anhydride (Cantharidin):

In the foregoing formula, n is a whole number from 2-10; the nitrogen,N, is part of the heterocyclic base, the remainder of the ring beingdesignated by box A."

The ring nitrogen of the heterocyclic base is included in CHI the exactformulation of structure to illustrate the site of L (L quaternary saltformation, the salts being formed from the bis-isoindole bases and X-represents an anion such I 0111/ 11, 0Q, OH l as I", Cl-, Br-, acetateor sulfate and R represents CHI i l lk l ou u h a ethyL a,w-Bis-(4,5,6,7tetrahydro-4 T-end0x y-1,2-dimethyl isolndo- In the formula the groupsrepresented by mm) mane damethomum salts (7) From 3 methyl 3,6endoxyhexahydrophthalic anhydride: A N- 011, CH: is the isoindoleobtained by reduction of the correspond- 2}. 32 i ing imides obtained byreaction of diamines with the following acid anhydrides: i AIH: 0%, CH i(1) Phthalic anhydride 2 cis-M-tetrahydrophthalic anhydride h3g3) iiii'iigfini' iiiii sifi (3) hexahydrophthalic anhydride (4) 3,6 endomethylenecis A4 tetrahydmphthalic (8) From 3,6-dimethyl-3,6-endoxyhexahydrophthalic anhydride anhydride:

(5) 3,6-endoxyhexahydrophthalic anhydride 5 CH:

(6) 1,2 dimethyl 3,6 endoxyhexahydrophthalic an- CH CH hydride(Cantharidin) (7) 3-rnethyl-3,fi-endoxyhexahydrophthalic anhydride \CH(8) 3,6 dimethyl 3,6 endoxyhexaphdrophthalic ani HI 0 I l hydride H. H.

(9) S-methyl hexahydrophthalic anhydride 6,211 domethylgnchexahydmphthalic anhydride oms-05,6355} tetrahydro-4 T-endox-4,7-dlmethyl lsoindomyl) alkane dimethon urn salts (9) From-methyl-hexahydrophthalic anhydride:

mw-Bis-(4,5,6,7,8,9-hexahydro-B-methyl-isoindolinyl) alkane dimethonlumsalts From 3,fi-endomethylene-hexahydrophthalic an- EXAMPLEI.-1,2-BIS-(-2-HEXAHYDROISO- INDOLINYL) ETHANE N-CHr-CHr-N CH CHr- Thebis-imide.-To 61.7 grams (0.4 mole) of hexahydrophthalic anhydridecontained in a flask fitted with reflux condenser were added 12.1 grams(0.2 mole) of ethylene diamine dissolved in 60 ml. of anhydrous benzene.The mixture was refluxed for an hour, the benzene distilled off and theresidue heated with stirring until a homogeneous melt was obtained. Thebis-amic acid thus obtained was cyclized to the bis-imide by heating for2 to 3 hours in an oil bath at 170 C. The solid was broken up andrecrystallized from benzene. The recrystallized product weighed 42grams, a 74% yield, and had a melting point of 140 C.; the nitrogencontent found by analysis was 8.27% as compared with an 8.43%theoretical nitrogen content.

The free base-40 grams (0.14 mole) of the bis-imide prepared abovedissolved in 300 ml. of absolute ethyl ether and dioxane was addeddropwise to a stirred solution of 23 grams (0.6 mole) of lithiumaluminum hydride dissolved in 800 ml. of anhydrous ether. The imide wasadded at a rate just sufiicient to maintain reflux of the ether. Oncompletion of the imide addition the mixture was stirred for two hourswith warming, if necessary to maintain reflux, and allowed to standovernight. The reaction mixtures was then decomposed by dropwiseaddition of water and stirred for several hours after adding a slightexcess of water. The inorganic material was removed by filtration andwashed with several portions of ether. The filtrate and washings weredried over anhydrous sodium sulfate (Na2SO4), the ether stripped off andthe residual oil vacuum distilled, yielding 25 grams, 78% yield, of theproduct having a boiling point of 120 to 130 C. at 0.01 mm. pressure.

The dihydrachloride.-Addition of a saturated ethanol solution of HCl tothe free base, as prepared above, in absolute methanol yielded acrystalline dihydrochloride, having a melting point of 2.94297 C.Recrystallization from absolute methanol-ether gave the dihydrochloridehaving a melting point of 300-310 C. and a chloride content of 20.25% ascompared with 20.30% theoretical.

The dimethiodide.-Addition of an excess of methyl iodide to the freebase dissolved in absolute methanol in a closed system and refrigerationproduced a crystalline dimethiodide melting at 260264 C.Recrystallization from absolute methanol and ether yielded the compoundwith melting point 269-271 C. calculated, 45.29%; found, 45.23%.

EXAMPLE lI.-l,6-BIS(2-HEXAHYDROISO- INDOLINYL) HEXANE The bis-imide.-Thebis-imide derived from hexamethylene diamine and hexahydrophthalicanhydride was prepared in 73% yield in a manner similar to that for thepreparation of the ethane homolog (Example I) and had the melting point78-81 C. Recrystallization from benzene-30-60 petroleum ether raised themelting point to 8 l-92.5 C.

Analytical data:

Iodide ion content:

Calculated,

Found, percent percent Oar hon Hydrogen- 2 N ltrogen see The freebase-The free base was obtained in 74% yield by lithium aluminum hydridereduction of the imide as described in Example I. It had a boiling pointwas obtained in a manner similar to that described under Example I andhad a melting point of 203-204 C. Chloride ion content: calculated,17.49%; found 17.54%.

The dimethiodide.-The dimethiodide was readily obtained as describedunder Example I and had a melting point of 246-247" C. which was changedonly slightly to 248-249 C. by recrystallization from absolute methanol.Iodide content: Calculated, 41.18%; found, 41.10%.

An alternative method of preparation comprises reacting the appropriateN-methyl substituted isoindole derivatives in a suitable solvent, forexample, methanol, ethanol, propanol, acetone, etc., with an alpha,omega dihalide. N-methyl substituted isoindole derivatives suitable foruse in this reaction are disclosed in volume 77 IACS page 616, 1955. Thereaction is exothermic; the products precipitate out and are thenrecrystallized from a suitable solvent. Following is an example of thisalternative method of synthesizing the novel compounds.

EXAMPLE III.-l,4-BIS-(-4,5,6,7,8,9- HEXAHYDRO- ISOINDOLINYL) BUTANEDIMETHONIUM DI- IODIDE.

A solution of 0.1 mole of butane diiodide was dissolved in 40 ml. ofisopropanol and added to a solution of 0.2 mole (27.8 grams) ofN-methyl-4,5,6,7,8,9 hexahydroisoindoline in 30 ml. of isopropanol. Thereaction mixture became warm at the outset. After standing for 8 hoursat room temperature, all solids formed were redissolved by warming andadding enough isopropanol to form a clear solution at its boiling point.The mixture was allowed to cool to room temperature and thenrefrigerated. The product was filtered oif and, when dried, has amelting point of 263-264 C. On recrystallization from absolute alcoholthe product melted at 266-267" C. The iodide ion calculated for theformula C22 H44 N2 I2 is 43.14% and that actually found was 43.07%.

The following Tables I, II and III give additional examples of compoundsprepared according to the present invention.

Table I BIB-HEXAHYDROISOINDOLINE ALKANE DIMETHONIUM SALTS cn, 0B,-

f' i on/ on Analysis per- Anal P eent iobic een idnie Melting iodideMelting bromide Alkane Formula point, 0. Formula D3165,

Oalou- Found Oalcu- Found lated lated Ethylene GeoHssNaI: 270-271 45. 2945. 23 CmHsaNEBrn 34. 27 Trimethyleue CnHmNz 73-274 44. 19 43. 97CMHMNIBH 284-285 33. 27 33. 24 CnHflNgIl 266-%7 43. 14 43. 07 CnHuNzBn290-291 32. 33 32.00 CaaHuNnI 290-291 42. 14 42. 19 CaaHuNaBn 284-23531. 44 31. 17 CuHmNaI: 250-252 41. 18 41. 27 CuHmNaBi 264-254 30. 59 30.45 CzrHnNzh 244. 5-225. 5 38. 55 38. 33 crwHuNzBrz 234-235 28. 31 28. 22CggHnN :12 217-213 37. 74 38. 09 CgaHsqNzBlr 237-238 27. 63 27. 44P-xylylene CaoHnNaBi: 269-270 29. 43 29.12

Table II BIS-4,7,8,9,-TETRAHYDROISOINDOLINE ALKANE DIMETHONIUM SALTS CH1011 (5H If-alkane-M 011/ 9 H Analysis r- Analysis percent 1011i cent,io'nic Melting iodide Melting bromide Alkane Formula point, 0. Formulappiit,

Oalcu- Found Calcu- Found lated leted Ethylene OinHaiNxBi'a 161-162 34.57 34. 36 Trlmethylene CnHeeNaIa 255-257. 5 44. 51 44. B0 CnHuNaBn250-251 33. 55 33. 70 Tctramethylene CMHasNzIl 2421-243 43. 4 43. 22OHHSINIBH 260-261 32. 59 32. 73 Pentamethylene CflHmNnI: 253-254 42. 4242. 56 CnHmNIBH 241-241. 5 31. 69 31. Hexamethylene CHHHNIII 232-233 41.41. 65 CnHnNzBrz 236-238 30. 83 30. 59 Nonamethyleue. CarHnNiIl 185.5-187 38. 7B 38. 80 C21H4sNiBrn 204-206 28. 52 28. 58 DecametliyleueCflHmNlII 213-214 37. 37. 66 CnHwNaBrz 208-209 27. 82 27.38 P-xylyleneCzeHuNaBl: 252-253 29. 69 29. 33

Table III selected from the group consisting of bis-isoindole quater-BIS-4,7-ENDOXY HEXAHYDROISOINDOLINE ALKANE These compounds may also beformed by the interaction of an alpha omega halogenated alkane and theappropriate N-mcthyl substituted isoindolc base employing a solvent suchas ace-tone, alcohol or acetonitrile.

This invention may be embodied in other specific forms Without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not re strictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are therefore intended to be embraced therein.

This application is a continuation in part of application Serial No,436, 725 filed April 5, 1954.

What is claimed and desired to be secured by United States LettersPatent is:

1. As a novel composition of matter, a compound nary salts having thegeneral structural formula in which n is a whole number from 2 to 10 andA is a ring system selected from the group of substituted andunsubstituted, saturated and unsaturated cyclic hydrocarbon ring systemsconsisting of:

. Cyclohexane Endoxycyclohexane Endomethylene cyclohexane 3-methylendoxycyclohexane 1,2-dimethylendoxycyclohexane3,o-dimethylendoxycyclohexane Cyclohexcne Endomethylene cyclohexeneS-methyl cyclohexane 10. Phenyl woommmpuN- toxic bis-methonium salthaving from 2 to 10 carbon atoms in the alkylene chain.

5. As a novel composition of matter, an alpha,omegabis-(4,5,6,7,8,9-hexahydro 4,7 endoxy 2 isoindolinyl) alkanenon-toxic bis-methoniurn salt having from 2 to 10 carbon atoms in thealkylene chain.

6. As a novel composition of matter, an alpha, omegabis-( 5,6,7,8,9-pentahydro-4,7 -endoxy-4-methy1 Z-isoindolinyl) alkanc non-toxicbis-methonium salt having from 2 to 10 carbon atoms in the alkylenechain.

7. As a novel composition of matter, the bismethonium bromide of1,2-bis-(4,5,6,7,8,9-hexahydno-2-isoindolinyl) ethane.

8. As a novel composition of matter, the bis-methonium bromide of1,3-bis-(4-rnethyl-4,7-endoxy-5,6,7,8,9-pentahydro-Z-isoindolinyl)propane.

9. As a novel composition of matter, the bis-methonium bromide of 1,3-bis-(4,7-dimethyl-4,7-end0xy-5,6,7,8,9- tetrwhydro-Z-isoindolinyl)propane.

10. As a novel composition of matter, the bis-methonium bomide o f1,10-bis-(4,7-endoxy-4,5,6,7,8,9-hexahydro-Z-isoindolinyl) decane.

11. As a novel composition of matter, the bis-methonium bromide ofl,3-bis-(4,7-endoxy4,5,6,7,8,9-hexahydro' 2-isoindo1iny1) propane.

References Cited in the file of this patent Beilstein: Hand. der Org.Chem, 4th ed., Band XX, 2nd suppL, page 171.

Jr. Am. Chem. Soc., vol. 75 pp. 4911-15 (1953).

1. AS A NOVEL COMPOSITION OF MATTER, A COMPOUND SELECTED FROM THE GROUPCONSISTING OF BIS-ISOINDOLE QUARTERNARY SALTS HAVING THE GENERALSTRUCTURAL FORMULA
 1. CYCLOHEXANE
 2. ENDOXYCYCLOHEXANE
 3. ENDOMETHYLENECYCLOHEXANE
 4. 3-METHYL ENDOXYCYCLOHEXANE 5.1,2-DIMETHYLENDOXYCYCLOHEXANE
 6. 3,6-DIMETHYLENDOXYCYCLOHEXANE 7.CYCLOHEXENE
 8. ENDOMETHYLENE CYCLOHEXENE
 9. 5-METHYL CYCLOHEXANE 10.PHENYL AND X IS A NON-TOXIC ANION